Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).

Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition.

OBJECTIVES: Epigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours. DESIGN: Alternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes. RESULTS: APBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using 'humanised mice' harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032). CONCLUSION: These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

Increasing anticholinergic burden and delirium in palliative care inpatients.

BACKGROUND: Delirium may complicate the hospital course and adversely impact remaining quality of life for palliative care inpatients. Medications with anticholinergic properties have been linked to delirium within elderly populations via serum anticholinergic assays. AIM: The aim of this study is to determine whether increasing anticholinergic burden, as measured using a clinical assessment tool, is associated with an increase in delirium among palliative care inpatients. DESIGN: This study was completed as a retrospective, case-control study. SETTING/PARTICIPANTS: Veterans admitted to the Veterans Affairs Boston Healthcare System and consulted to the palliative care service were considered for inclusion. Increase in anticholinergic burden from admission through hospital day 14 was assessed using the Anticholinergic Risk Scale. Presence of delirium was determined by use of a validated chart review instrument. RESULTS: A total of 217 patients were analyzed, with a mean age of 72.9 (±12.8) years. The overall delirium rate was 31% (n = 67). Patients with an increase in Anticholinergic Risk Scale (n = 72 (33%)) were 40% more likely to experience delirium (odds ratio = 1.44, 95% confidence interval = 1.07-1.94) compared to those without increase (n = 145 (67%)). After adjustment for age, brain metastasis, intensive care unit admission, illness severity, opiate use, and admission Anticholinergic Risk Scale using multivariable modeling, delirium risk remained significantly higher in patients with an Anticholinergic Risk Scale increase compared to those without increase (adjusted odds ratio = 1.43, 95% confidence interval = 1.04-1.94). CONCLUSION: An increase in Anticholinergic Risk Scale from admission was associated with delirium in palliative care inpatients. While additional study is needed, anticholinergic burden should be increased cautiously in palliative inpatients, and those with increases should be closely followed for delirium.

The perceived value of a geriatrics-surgery co-management program: Perspectives from three surgical specialties.

BACKGROUND: Geriatrics-surgery co-management (GSCM) programs have improved patient outcomes, but little is known about how they change care and whether their value varies by surgical specialty. We aimed to assess GSCM's effects as perceived by Orthopedic Trauma, Trauma, and Neurosurgery clinicians. METHODS: We conducted a mixed-methods study utilizing electronic survey and virtual interviews at Penn Presbyterian Medical Center, an academic trauma center, in Philadelphia, PA. Participants included physicians, advanced practice providers, nurses, social workers, and case managers in the aforementioned specialties. Key measures were perspectives on value of GSCM, its facilitators, specialty most appropriate to manage specified medical issues, and factors affecting use. RESULTS: Of 71 eligible clinicians, 45 (63%) completed the survey and 12 (21%) of 56 purposefully sampled for specialty-role diversity were interviewed. Clinicians across specialties valued GSCM highly and similarly for impact on personal management of older adults (grand mean [standard error, SE] = 4.33 [0.24] out of 5; p = 0.80 for specialty means comparisons), patient care (mean [SE] = 4.47 [0.21]; p = 0.27), patient outcomes (mean [SE] = 4.26 [0.22]; p = 0.51), and specialty overall (mean [SE] = 4.55 [0.23]; p = 0.25) but less so for knowledge growth (mean [SE] = 3.47 [0.29]; p = 0.11). Interviewees across specialties reported that value derived from improved understanding of patient history, management of complex medical conditions, goals of care support, communication with families, and patient discharge facilitation. Interviewees also agreed on program facilitators: aligned stakeholders, shared data-driven goals, champion/administrative support, continuity and availability of geriatricians, and thorough communication. Specialties differed on three issues: (1) who should manage some medical concerns; (2) whether GSCM makes their job easier (significantly easier for Orthopedic Trauma: mean [SE] = 4.75 [0.29] vs. Trauma: mean [SE] = 4.01 [0.19]; p = 0.05); and (3) whether GSCM increases coordination difficulty (more for Neurosurgery: mean [SE] = 2.18 [0.0.58] vs. Orthopedic Trauma: mean [SE] = 0.51 [0.42]; p = 0.03 and Trauma: mean [SE] = 0.89 [0.28]; p = 0.07). Orthopedic Trauma had the most positive impression of GSCM overall. CONCLUSIONS: Clinicians across diverse surgical specialties valued GSCM. Hospitals considering implementation or expansion of GSCM should attend to identified facilitators and may need to tailor to specialty.

Improving medication management competency of clinical trainees in geriatrics.

The authors hypothesized that an interprofessional workshop would improve geriatrics trainees' medication management. The workshop was based on a needs assessment and comprised an interactive session with pharmacists on managing medications in elderly adults. Participants were trainees in their geriatrics rotation at a tertiary care medical center. Trainees completed a medication appropriateness survey for three patients, one of which was their own. After the workshop, trainees reviewed medications of the three patients. Trainees completed online surveys after their rotation and 3 months later. Of 95 trainees rotating through geriatrics, 76 (80%) attended the workshop and completed the worksheet. Trainees' scores on reviewing medication lists improved significantly, from 6.7±2.3 to 7.7±2.0 out of 11 for standardized patient 1 (P<.001) and from 5.7±1.8 to 6.4±1.5 out of 11 for standardized patient 2 (P=.009). Trainees' scores on their own patients' lists also improved significantly, from 5.6±1.5 to 6.6±1.5 out of 10 (P<.001). After the workshop, 95% (71/75) planned to change the medication regimen of the patient they presented, and 93% (68/73) planned to change other patients' medications based on information learned during the workshop. Three months later, 35% (12/34) had made changes to the regimen of the patient they discussed during the workshop, and 71% (15/21) had made changes to other patients' regimens. Seventy-eight percent (18/23) rated the workshop as the top nonclinical experience of their geriatrics rotation. In conclusion, this interprofessional medication management workshop improved trainees' ability to perform medication reviews accurately and led to change in self-reported prescribing behavior.

Complexity perplexity: a systematic review to describe the measurement of medication regimen complexity.

INTRODUCTION: Complex medication regimens are error prone and challenging for patients, which may impact medication adherence and safety. No universal method to assess the complexity of medication regimens (CMRx) exists. The authors aim to review literature for CMRx measurements to establish consistencies and, secondarily, describe CMRx impact on healthcare outcomes. AREAS COVERED: A search of EMBASE and PubMed for studies analyzing at least two medications and complexity components, among those self-managing medications, was conducted. Out of 1204 abstracts, 38 studies were included in the final sample. The majority (74%) of studies used one of five validated CMRx scales; their components and scoring were compared. EXPERT OPINION: Universal CMRx assessment is needed to identify and reduce complex regimens, and, thus, improve safety. The authors highlight commonalities among five scales to help build consensus. Common components (i.e., regimen factors) included dosing frequency, units per dose, and non-oral routes. Elements (e.g., twice daily) of these components (e.g., dosing frequency) and scoring varied. Patient-specific factors (e.g., dexterity, cognition) were not addressed, which is a shortcoming of current scales and a challenge for future scales. As CMRx has important outcomes, notably adherence and healthcare utilization, a standardized tool has potential for far-reaching clinical, research, and patient-safety impact.

Aging, antiretrovirals, and adherence: a meta analysis of adherence among older HIV-infected individuals.

INTRODUCTION: Older adults are generally considered to be at greater risk for medication non-adherence due to factors such as medication complexity, side effects, cost, and cognitive decline. However, this generalization may not apply to older adults with human immunodeficiency virus (HIV). Regardless of age, suboptimal adherence to antiretroviral therapy (ART) can lead to increased viral load, immunosuppression, drug-resistant viral strains, co-morbidities, and opportunistic infections. Understanding trends of adherence to ART among older adults is critical, especially as the population of people living with HIV grows older. OBJECTIVES: The purpose of this systematic review and meta-analysis is to determine if older individuals with HIV are less likely to be non-adherent to antiretroviral therapy than younger individuals with HIV. DESIGN: A systematic search in PubMed, Embase, and PsycINFO was conducted to identify peer-reviewed articles evaluating adherence to ART in older adults. Two independent reviewers screened abstracts, applied inclusion criteria, and appraised study quality. The bibliographies of qualifying studies were searched. Data were abstracted from studies by two independent authors. Meta-analyses were conducted, and adherence levels were reported as the relative risk of non-adherence in older individuals compared to younger individuals. RESULTS: The systematic search yielded 1,848 abstracts. Twelve studies met full inclusion criteria. The overall meta-analysis found that older age reduced risk for nonadherence by 27 % (relative risk (RR) 0.72, 95 % confidence interval (CI) 0.64­0.82). Studies assessing both short-term and long-term adherence demonstrated a significant reduction in non-adherence among older patients (RR 0.75, 95 % CI 0.64­0.87 and RR 0.65, 95 % CI 0.50­0.85, respectively). CONCLUSIONS: Older adults with HIV have a reduced risk for non-adherence to ART than their younger counterparts. Future studies should seek to elucidate contributing factors of adherence among older individuals with HIV.

The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review.

AIMS: To review recent evidence that suggests inflammation plays a similar role in the pathogenesis of delirium and dementia. METHODS: We performed a literature search of original research and review articles in PubMed using the keywords: delirium, dementia, and inflammation. We summarized the evidence linking inflammation to the pathogenesis of delirium and dementia. DISCUSSION: Delirium and dementia share similarities in clinical and pathogenic features, leading to the speculation that instead of being distinct clinical entities, the two age-related conditions may be linked by a common pathogenic mechanism. Inflammatory markers have been shown to be elevated in both delirium and dementia, thereby implicating inflammation as a possible mediating factor in their genesis. There is evidence in both basic science and clinical research literature that elevated cytokines play a crucial role in the development of cognitive dysfunction observed in both dementia and delirium. CONCLUSION: Mounting evidence supports the role of inflammation in the development of both dementia and delirium. Further studies are needed to elucidate the mechanisms underlying these relationships.

An educational intervention for providers to promote bone health in high-risk older patients.

OBJECTIVES: To design, implement, and assess an educational intervention for providers focused on osteoporosis screening and management in older patients with chronic obstructive pulmonary disease or asthma who have been prescribed prolonged courses of oral or high-dose inhaled corticosteroids or both and are therefore at high risk for bone loss and fractures. DESIGN: One-group pretest-posttest. SETTING: Academic outpatient pulmonary practice. PARTICIPANTS: Nineteen pulmonary specialists at an academic medical center. INTERVENTION: Educational theory and a needs assessment and attitude survey guided the development of a multicomponent educational intervention. MEASUREMENTS: Change in provider behavior was assessed by auditing the electronic medical records for adherence to osteoporosis management guidelines in high-risk patients seen by participants at baseline and for 6 months after the educational intervention. Knowledge transfer and changes in attitude were assessed using pre- and posttests and surveys. RESULTS: A 19% increase in overall rate of adherence to osteoporosis management guidelines in high-risk patients was observed: 45% before intervention to 64% after intervention (n=249 patients, P=.003). Postintervention surveys and test scores also showed statistically significant gains from baseline. CONCLUSION: An educational intervention improved adherence to osteoporosis management guidelines of academic pulmonary specialists. The results of this study provide evidence for the positive effect of a multimodal educational program in altering practice behaviors.

HIV in older adults.

The prevalence of HIV/AIDS in older adults continues to increase, and in 2005, 25% of those infected with HIV were older than 50. Successful treatment regimens allow people to live longer with HIV, but the incidence is also increasing, with older adults accounting for 15% of new HIV cases in 2005. Prevention, diagnosis, and management of HIV/AIDS in older adults are complex issues. The aging immune system may impact response to treatment with highly active antiretroviral therapy (HAART), and there is greater potential for drug-drug interactions and toxicities due to comorbidities and polypharmacy. Patients living longer with HIV are more likely to develop diseases associated with aging, and at an earlier age, than those without HIV. These include coronary artery disease, dyslipidemia, metabolic syndrome, diabetes, osteoporosis, and dementia. Geriatricians and primary care providers are increasingly responsible for managing these complex issues.